1. MOLECULAR MECHANISM OF DRUG
ACTION
• Calcium &
Phosphatidyl-
inositol
• PRESENTED BY :
• SHAVYA SINGH
• M.PHARM 1ST YEAR
• (PHARMACOLOGY)

2. Calcium :
• Important messenger in all cells .
• Regulate diverse responses including gene
expression ,contraction, secretion, metabolism &
electrical activity.
• Calcium can enter cell through calcium channels
in plasma membrane or released by hormones or
growth factors from intracellular stores.

3. Types of calcium channels:
In the cell membranes their are three types of
calcium channels:
 Voltage-dependent (L, N, P, Q,R, T)
 Receptor operating.
 Stretch activated.

4. Calcium channels
L-TYPE P-TYPE N-TYPE R-TYPE T-TYPE
HVA(high voltage Intermediate voltage
(HVA) (HVA) Low voltage activated
activated) activated
Purkinje neurons in
Skeletal muscles ,smooth Brain & peripheral Cerebellar granule cells &
cerebellum/cerebellar Neurons & bones
muscles,bone,dendrites . nervous system other neurons
granules cells

5. Calcium channel blockers
• Block calcium channels (L-type) in heart and blood
vessels
• prolong depolarisation
• ↑QRS width
• block SA and AV node conduction
• heart block
• asystole
• vasodilators
• cerebral protection

6. Calcium channel blockers
• Hypotension
• peripheral vasodilatation and myocardial depression
• Bradycardia
• AV and SA node block

7. Calcium antagonists reduce coronary and
peripheral vascular resistance, decrease
blood pressure and myocardial oxygen
consumption.
Dihydro pyridines (nifedipine , amlodipine etc)
don’t have negative inotropic , chrono-
tropic and dromotropic effect in comparison to
verapamil and diltiazem, which increase
baroreflex sensibility.

8. Regulation of intra-cellular calcium

9. REGULATION OF INTRACELLULAR CALCIUM
[Ca 2+]ext
(1000mM)
Ca2+ATPase Pi
[Ca2+]er [Ca 2+]cyt [Ca 2+]m
[CaX]
(100mmoles) (0.1mM) ( 0.1mM) H+ ( 100mmoles)
[H+] [Na+] [K+]
CaM
ATPase ATPase
-
GLUCAGON [H+] Ca 2+ [Na+] [K+]
a2-ADRENERGIC
b-ADRENERGIC
VASOPRESSIN

10. MITOCHONDRIAL CALCIUM TRANSPORT
DILTIAZEM CYTOSOL
RUTHENIUM
RED [Ca 2+]c [2Na+]c [2H+]c [Ca 2+]c
ELECTRO-
ELECTROGENIC 0.5mM
NEUTRAL
-180mV
DpH [Ca 2+]m [2Na+]m [2H+]m [Ca 2+]m
0.1mM Ca2+ MATRIX
 MATRIX CALCIUM PYRUVATE DEHYDROGENASE PHOSPHATASE
(0.8-1mM) ISOCITRATE DEHYDROGENASE
2-OXOGLUTARATE DEHYDROGENASE
PYRUVATE OXIDATION AND TCA CYCLE ACTIVITY
PYROPHOSPHATASE ACTIVITY
INCREASED PYROPHOSPHATE LEADS TO SWELLING, ACTIVATION OF
RESPIRATORY CHAIN, INCREASED ADENINE NUCLEOTIDE CONTENT AND
INCREASED ATP/ADP RATIO.

11. CONTROL OF CALCIUM ENTRY INTO CELLS
TRP FAMILY
OF PROTEINS
(Ca2+ CHANNEL)
CIF (IP4?)
RYANODINE
RECEPTORS

12. The Structure and Function of the
Calcium-Calmodulin Complex
Kinases
Phosphatases

13. Ca Vascular smooth muscle
channel
s
Ca AT
(intracellul
Calmo P b agonists
ar) dulin
Ca - cA
calmodulin MPProteinkinase A
complex
MLCK*
Myosin-LC kinase (MLCK) MLCK-(PO
Myosin Myosin-LC- PO
Myosin-LC
light chain
(Myosin- Actin
LC)
Contraction Relaxation

14. Phosphatidyl inositol

15. • Phosphatidyl inositol is a negatively
charged phospholipid and a minor component in the
cytosolic side of eukaryotic cell membranes.
• The inositol can be phosphorylated to form phosphatidyl
inositol phosphate (PIP), phosphatidyl inositol bi-
phosphate (PIP2) and phosphatidyl inositol tri-
phosphate (PIP3).
• PIP, PIP2 and PIP3 are collectively called
phosphoinositides.

16. LOCATION :
• Phosphatidylinositol is especially abundant in brain
tissue, where it can amount to 10% of the phospholipids,
but it is present in all tissues and cell types.
BIOSYNTHESIS :
• PI is formed biosynthetically from precursor cytidine
diphosphate diacylglycerol by reaction with inositol and catalysed
by the enzyme CDP-diacylglycerol inositol phosphatidyl transferase
(phosphatidyl inositol synthase )
• the other product of the reaction is cytidine mono-phosphate (CMP).
• The enzyme is located in the endoplasmic reticulum mainly,
although it may also occur in the plasma membrane in yeasts, and
almost entirely on the cytosolic side of the bilayer.
• PI is then delivered to other membranes either by vesicular transport
or via the agency of specific transfer proteins.

18. Types of phosphatidyl-inositol
 PI-MONOPHOSPHATE
• Phosphatidylinositol 3-phosphate
• Phosphatidylinositol 4-phosphate
• Phosphatidylinositol 5-phosphate
 PI-BIPHOSPHATE
• Phosphatidylinositol 3,4-bisphosphate
• Phosphatidylinositol 3,5-bisphosphate
• Phosphatidylinositol 4,5-bisphosphate
 PI-TRIPHOSPHATE
• Phosphatidylinositol 3,4,5-triphosphate

19. Three Types of Inositol phospholipids
PI, PI(4)P, PI(4,5)P2

20. Phospholipase C-b
(PLC-b) Produces
DAG
(diacylglycerol) and
IP3 (inositol 1,4,5-
trisphosphate (IP3))
Gq->PLC-b

21. PHOSPHOLIPASE Cb ACTIVATION
Ca2+
H
PHOSPHATIDYL
INOSITOL 4,5- 1,2-DIACYL
PHOSPHO- GLYCEROL
LIPASE Cb BISPHOSPHATE
Active
g aq P OH
Ca2+ P PIP2
b GTP PKC
P ACTIVE
P
IP3-DEPENDENT P IP3
Ca2+ CHANNEL
P
ARACHIDONIC
Ca2+
ACID
E + Cal2 + 4Ca2+ ECal2(Ca2+)4
Ca2+
ENDOPLASMIC PHYSIOLOGICAL RESPONSE
RETICULUM

22. HYDROLYSIS OF PHOSPHATIDYL INOSITOL
4,5 BISPHOSPHATE
O OH
1,2-DIACYLGLYCEROL O P O
OH PHOSPHATIDYLINOSITOL
O- OH OH RAPID BREAKDOWN
OH FOLLWED BY RESYNTHESIS
O OH
1,2-DIACYLGLYCEROL O P O PHOSPHATIDYLINOSITOL-
OH 4 PHOSPHATE
O- OH OH
OPO32-
O OPO32-
1,2-DIACYLGLYCEROL O P O
OH PHOSPHATIDYLINOSITOL-
O- OH OH 4,5 BISPHOSPHATE
OPO32-1-2% OF TOTAL INOSITOL
SITE OF HYDROLYSIS LIPIDS

23. METABOLISM OF PHOSPHATIDYL INOSITOL
4,5 BISPHOSPHATE
R1
R2 O OPO32-
DIACYLGLYCEROL
O P O R1
OH *ARACHIDONIC
O- OH OH R2* ACID
OPO32- OH
PI 4,5P2
PHOSPHOLIPASE C
OPO32- OH
2-O 2-O
3PO 3PO
OH PHOSPHATASE OH
OH OH OH OH
OPO32- OPO32-
Ins (1,4,5)P3 Ins (1,4,)P2
Ca2+-DEPENDENT
KINASE
OPO32- OH
2-O 2-O
3PO 3PO
OH PHOSPHATASE OH
OH OPO32- OH OPO32-
OPO32- OPO32-
Ins (1,3,4,5)P4 Ins (1,3,4)P3

24. RECEPTOR-STIMULATED BREAKDOWN
OF PHOSPHATIDYL INOSITOL 4,5 BISPHOSPHATE
PtdINS 4,P PtdINS 4,5P2
(RAPID DEPLETION) (RAPID DEPLETION)
GTP STIMULUS
Ca2+ INDEPENDENT
1,2 DIACYLGLYCEROL Ins 1,4,5 P3
(RAPID ACCUMULATION) (RAPID ACCUMULATION)
32P-ATP
Ins 1,4 P2
PHOSPHATIDATES (ACCUMULATION)
(ACCUMULATES,
STIMULATED 32P
LABELLING)
Ins 1 P
(ACCUMULATION)
PHOSPHATIDYL-CMP
INHIBITED BY Li+
Ptd INOSITOL INOSITOL
(DEPLETED, STIMULATED (SLOW ACCUMULATION)
32P LABELLING)

25. CALCIUM RELEASE BY INSOSITOL PHOSPHATES
RELEASE OF CALCIUM REQUIRES THE 4,5 PHOSPHATE
GROUPS IN THE MOLECULE
Ins1,4P2 IS INEFFECTIVE
Ins4,5P2 IS WEAK
Ins2,4,5P3 IS EFFECTIVE BUT LESS SO THAN Ins1,4,5P3
HORMONAL STIMULATION RESULTS IN THE PRODUICTION
OF TWO INOSITOL TRIS PHOSPHATES Ins1,4,5 P3 AND
Ins1,3,4 P3